Abstract
Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.
Highlights
Doxorubicin (DOX) belongs to the family of anthracyclines, and has been used to against cancer since late 1960s
The decrease in the ratio of heart weight to body weight due to DOX treatment was alleviated by diosgenin in the DOX plus diosgenin group comparing to the DOX group (p < 0.05)
Serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB) were significantly elevated in the DOX alone treated group as compared with the control (p < 0.05)
Summary
Doxorubicin (DOX) belongs to the family of anthracyclines, and has been used to against cancer since late 1960s. Multiple mechanisms are involved in DOX induced cardiomyopathy, such as the increase in cardiac oxidative stress and lipid peroxidation, and changes in adenylate cyclase activity leading to apoptosis and inflammation-related signaling pathway [5,6]. Previous studies indicated that a supplementation of food rich in diosgenin, such as a yam variety (called air potato), has been shown to possess the protective effect on myocardial I/R injury in rats due to apoptosis and necrosis [22]. The recent study found that diosgenin abrogated production of intracellular ROS [24] Another finding suggests that diosgenin has a beneficial role against aortic remodeling induced by oxidative stress in diabetic state and decreases the lipid peroxidation in aorta [25]. Based on the potential role of diosgenin in ameliorating oxidative stress and injury, we attempted to evaluate the beneficial effects of diosgenin against the DOX-induced cardiotoxicity in mice
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